In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras
- Cincinnati Children's Hospital Medical Center, United States
Abstract
Generation of bone marrow (BM) from embryonic stem cells (ESCs) promises to accelerate the development of future cell therapies for life-threatening disorders. However, such approach is limited by technical challenges to produce a mixture of functional BM progenitor cells able to replace all hematopoietic cell lineages. Herein, we used blastocyst complementation to simultaneously produce BM cell lineages from mouse ESCs in a rat. Based on FACS analysis and single-cell RNA sequencing, mouse ESCs differentiated into multiple hematopoietic and stromal cell types that were indistinguishable from normal mouse BM cells based on gene expression signatures and cell surface markers. Receptor-ligand interactions identified Cxcl12-Cxcr4, Lama2-Itga6, App-Itga6, Comp-Cd47, Col1a1-Cd44 and App-Il18rap as major signaling pathways between hematopoietic progenitors and stromal cells. Multiple hematopoietic progenitors, including hematopoietic stem cells (HSCs) in mouse-rat chimeras derived more efficiently from mouse ESCs, whereas chondrocytes predominantly derived from rat cells. In the dorsal aorta and fetal liver of mouse-rat chimeras, mouse HSCs emerged and expanded faster compared to endogenous rat cells. Sequential BM transplantation of ESC-derived cells from mouse-rat chimeras rescued lethally-irradiated syngeneic mice and demonstrated long-term reconstitution potential of donor HSCs. Altogether, a fully functional bone marrow was generated from mouse ESCs using rat embryos as 'bioreactors'.
Data availability
Bone marrow single cell RNA sequencing data have been deposited in GEO under accession number GSE184940.
Article and author information
Author details
Vladimir V Kalinichenko
Funding
National Heart, Lung, and Blood Institute (HL141174)
- Vladimir V Kalinichenko
National Heart, Lung, and Blood Institute (HL149631)
- Vladimir V Kalinichenko
National Heart, Lung, and Blood Institute (HL152973)
- Vladimir V Kalinichenko
National Heart, Lung, and Blood Institute (HL158659)
- Tanya V Kalin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee of the Cincinnati Children's Research Foundation (protocol # IACUC2016-0038).
Copyright
© 2022, Wen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras
eLife 11:e74018.
https://doi.org/10.7554/eLife.74018
